Are sporadic colorectal cancers in young patients distinct from those in elderly patients?

AIM: The aim of this study was to compare the clinicopathological and oncological characteristics of sporadic colorectal cancer (CRC) between young and elderly patients without any genetic mutations that cause hereditary CRC. METHOD: In this cross-sectional, retrospective study conducted at three tertiary referral hospitals, we enrolled 1599 patients with CRC who underwent surgery between January 2010 and December 2017, including 157 young patients (age ≤ 40 years; yCRC) and 1442 elderly patients (age ≥ 70 years; eCRC). The clinicopathological and oncological outcomes were compared between the two groups. RESULTS: The median age at diagnosis was 37 years in the yCRC group (range 33.0-39.2 years) and 76 years in the eCRC group (range 72.0-79.0 years). The yCRC group did not present with advanced stages at diagnosis compared with the eCRC group, and the distribution of tumour stages was similar between the two groups. Microsatellite instability (MSI) testing revealed no difference in the frequency of tumours with high MSI (7.8% in yCRC, 5.8% in eCRC), and the frequency of mutations in the KRAS, NRAS and BRAF genes was also similar. The 3-year overall survival was better in the yCRC group than in the eCRC group (97.4% vs. 83.5%, p < 0.001); however, no such difference was observed in cancer-specific survival. CONCLUSION: Genetically proven sporadic CRCs did not differ significantly between young and elderly patients in terms of tumour stage, tumour location and various molecular features. CLINICAL TRIAL REGISTRATION NUMBER: The study was retrospectively registered with Clinical Trials.gov (no. NCT05601609).

SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit.

SH2B1 mutations are associated with obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) in humans. Global deletion of Sh2b1 results in severe obesity, type 2 diabetes, and MASLD in mice. Neuron-specific restoration of SH2B1 rescues the obesity phenotype of Sh2b1-null mice, indicating that the brain is a main SH2B1 target. However, SH2B1 neurocircuits remain elusive. SH2B1-expressing neurons in the paraventricular hypothalamus (PVHSH2B1) and a PVHSH2B1→dorsal raphe nucleus (DRN) neurocircuit are identified here. PVHSH2B1 axons monosynaptically innervate DRN neurons. Optogenetic stimulation of PVHSH2B1 axonal fibers in the DRN suppresses food intake. Chronic inhibition of PVHSH2B1 neurons causes obesity. In male and female mice, either embryonic-onset or adult-onset deletion of Sh2b1 in PVH neurons causes energy imbalance, obesity, insulin resistance, glucose intolerance, and MASLD. Ablation of Sh2b1 in the DRN-projecting PVHSH2B1 subpopulation also causes energy imbalance, obesity, and metabolic disorders. Conversely, SH2B1 overexpression in either total or DRN-projecting PVHSH2B1 neurons protects against diet-induced obesity. SH2B1 binds to TrkB and enhances brain-derived neurotrophic factor (BDNF) signaling. Ablation of Sh2b1 in PVHSH2B1 neurons induces BDNF resistance in the PVH, contributing to obesity. In conclusion, these results unveil a previously unrecognized PVHSH2B1→DRN neurocircuit through which SH2B1 defends against obesity by enhancing BDNF/TrkB signaling.

Complete Obstruction, a Real Risk Factor: A Comprehensive Study on Obstruction in Stage IIA Colon Cancer With Propensity Score Matching Analysis.

MICROABSTRACT: This study evaluates the prognostic significance of obstructions in stage IIA colon cancer, distinguishing between partial and complete obstructions. It employs a retrospective review of 1914 patients with propensity score matching to analyze oncologic outcomes. Findings reveal complete obstruction as a significant risk factor for poorer outcomes, emphasizing the necessity for further research to refine treatment strategies, particularly regarding the efficacy of adjuvant chemotherapy across obstruction types. BACKGROUND: This study examined the prognostic impact of obstructions in stage IIA colon cancer. The analysis specifically differentiated partial and complete obstructions, analyzing their distinct influences of both on oncologic outcomes. MATERIALS AND METHODS: A retrospective review was conducted of stage IIA colon cancer cases with the presence of an obstruction. Patients were stratified by whether it was partial or complete based on the severity of obstruction. Propensity score matching was employed to control for confounders. RESULTS: Among 1914 consecutive patients diagnosed with stage IIA colon cancer, 758 patients (597 patients with partial obstruction, 161 patients with complete obstruction) exhibited obstruction, while 1156 patients had no obstruction. The median follow-up period was 126 months. Complete obstruction was associated with poorer disease-free survival (Hazard ratio (HR) = 1.785, P < .001) and overall survival (HR = 1.853, P = .001). This trend persisted after propensity score matching, patients with complete obstruction showing a worsened disease-free survival (HR = 1.666, P = .028) and overall survival (HR = 1.732, P = .041). Adjuvant chemotherapy showed improved outcomes overall, but its efficacy varied across obstruction types. CONCLUSION: Differentiating between complete and partial obstructions in stage IIA colon cancer is an important clinical distinction, as our findings suggest that complete obstruction is a significant risk factor for poorer oncologic outcomes. While adjuvant chemotherapy generally improves prognosis in stage IIA colon cancer, the correlation of obstruction type with its efficacy remains uncertain, necessitating further research to refine treatment strategies.

Risk factors for the failure of endoscopic balloon dilation to manage anastomotic stricture from colorectal surgery: retrospective cohort study.

BACKGROUND: An anastomotic stricture after colorectal surgery is principally managed by endoscopic balloon dilation (EBD). Although this intervention is effective, however, subsequent procedures or surgical interventions are often required. This study aimed to assess the long-term outcomes of EBD for anastomotic stricture arising from colorectal cancer surgery. MATERIALS AND METHODS: We analyzed 173 patients who received curative surgery for colorectal cancer at our hospital between January 2000 and December 2022 and had undergone EBD to manage anastomotic stricture. The medical records of these cases were retrospectively reviewed to assess the outcomes and risk factors for restenosis and permanent stoma. RESULTS: Of the 173 study patients, 41 (23.7%) presented with restenosis with a median time to recurrence of 49 [37-150] days. The restenosis group was significantly younger (55.6 years versus 60.8 years), with a more prominent rectal location (80.5% versus 57.6%), a higher incidence of hand-sewn anastomosis (24.4% versus 5.3%), and a higher percentage of neoadjuvant radiotherapy (34.1% versus 5.3%, P < 0.001). Multivariable analysis indicated neoadjuvant radiotherapy (adjusted HR 2.48; 95% CI 1.03-5.95) and cerebral vascular disease (adjusted HR 6.97; 95% CI 2.15-22.54) as independent prognostic factors for restenosis. Fourteen patients (8.1%) required a permanent stoma due to treatment failure. All cases needing a permanent stoma were male (14 patients, 100%, P = 0.007) and this group had a higher rate of neoadjuvant radiotherapy, adjuvant chemotherapy, and hand-sewn anastomosis. CONCLUSION: Patients receiving neoadjuvant radiotherapy are most prone to restenosis after an EBD intervention to manage an anastomotic stricture. Neoadjuvant radiotherapy is also a strong risk factor for requiring a permanent stomas due to treatment failure.

Short-term outcomes of da Vinci SP versus Xi for colon cancer surgery: a propensity-score matching analysis of multicenter cohorts.

Recent advancements in robotic systems have led to the introduction of the da Vinci SP system, which allows surgeons to perform colon cancer surgery through fewer ports. This study aimed to evaluate the perioperative outcomes of colon cancer surgeries conducted using the da Vinci SP and Xi systems. Patients who underwent robotic colon cancer surgeries between November 2020 and December 2022 at two tertiary referral centers were considered for inclusion. Following propensity-score matching, short-term outcomes between the two systems were retrospectively analyzed. Out of 189 patients included in the study, 106 from 53 propensity-score matched pairs were analyzed. Patients operated on with the SP system exhibited smaller incision lengths (5.0 cm vs. 9.4 cm, p < 0.001) experienced less pain at 8 h (3.0 vs. 3.5, p < 0.001) and at 24 h post-operation (2.9 vs. 3.3, p = 0.001) and had a shorter duration of hospital stay (5 days vs. 6 days, p = 0.002). The overall rate of postoperative complications was 10.4%, with no significant difference between the SP and Xi groups (7.5% vs. 13.2%). Robotic-assisted colon cancer surgery using the da Vinci SP system is feasible and demonstrates favorable short-term outcomes. Compared to the Xi system, the SP system offers advantages in terms of cosmesis, postoperative pain, and recovery duration for colon cancer patients.

Robot-assisted lateral pelvic lymph node dissection in patients with advanced rectal cancer: a single-center experience of 65 cases.

The treatment of lateral pelvic lymph node (LPLN) metastasis of rectal cancer has evolved because of technical difficulties from open surgery to laparoscopy and, recently, robot-assisted surgery. This study aimed to evaluate the technical feasibility and short- and long-term outcomes of robot-assisted LPLN dissection (LPND) following total mesorectal excision (TME) in advanced rectal cancer. Clinical data of 65 patients who underwent robotic-assisted TME with LPND from April 2014 to July 2022 were reviewed. Data regarding operative details, postoperative morbidity (within 90 postoperative days) for short-term outcomes and lateral recurrence as long-term outcomes were analyzed. Among the 65 patients with LPND, preoperative chemoradiotherapy was performed in 49 (75.4%). The mean operative time was 306.8 (range 191-477) min, and the mean time of unilateral LPND was 38.6 (range 16-66) min. LPND was bilaterally performed in 19 (29.2%) patients. The mean number of each side of harvested LPLNs was 6.8. Lymph node metastasis was observed in 15 (23.0%) patients, and 10 (15.4%) patients had postoperative complications. Lymphocele (n = 3) and pelvic abscess (n = 3) were the most common, followed by voiding difficulty, erectile dysfunction, obturator neuropathy, and sciatic neuropathy (all n = 1). During the 25 months of median follow-up, no lateral recurrence of the LPND site was noted. Robot-assisted LPND following TME is safe and feasible and showed acceptable short- and long-term outcomes. Despite some study limitations, we may be able to apply this strategy more widely through subsequent prospective controlled studies.

Universal Screening for Lynch Syndrome Compared with Pedigree-Based Screening: 10-Year Experience in a Tertiary Hospital.

PURPOSE: Universal screening for Lynch syndrome (LS) refers to routine tumor testing for microsatellite instability (MSI) among all patients with colorectal cancer (CRC). Despite its widespread adoption, real-world data on the yield is lacking in Korean population. We studied the yield of adopting universal screening for LS in comparison with pedigree-based screening in a tertiary center. MATERIALS AND METHODS: CRC patients from 2007-2018 were reviewed. Family histories were obtained and were evaluated for hereditary nonpolyposis colorectal cancer (HNPCC) using Amsterdam II criteria. Tumor testing for MSI began in 2007 and genetic testing was offered using all available clinicopathologic data. Yield of genetic testing for LS was compared for each approach and step. RESULTS: Of the 5,520 patients, tumor testing was performed in 4,701 patients (85.2%) and family histories were obtained from 4,241 patients (76.8%). Hereditary CRC (LS or HNPCC) was present in 69 patients (1.3%). MSI-high was present in 6.9%, and 25 patients had confirmed LS. Genetic testing was performed in 41.2% (47/114) of MSI-high patients, out of which 40.4% (19/47) were diagnosed with LS. There were six additional LS patients found outside of tumor testing. For pedigree-based screening, Amsterdam II criteria diagnosed 55 patients with HNPCC. Fifteen of these patients underwent genetic testing, and 11 (73.3%) were diagnosed with LS. Two patients without prior family history were diagnosed with LS and relied solely on tumor testing results. CONCLUSION: Despite widespread adoption of routine tumor testing for MSI, this is not a fail-safe approach to screen all LS patients. Obtaining a thorough family history in combination with universal screening provides a more comprehensive 'universal' screening method for LS.

LepRb+ cell-specific deletion of Slug mitigates obesity and nonalcoholic fatty liver disease in mice.

Leptin exerts its biological actions by activating the long-form leptin receptor (LepRb). LepRb signaling impairment and leptin resistance are believed to cause obesity. The transcription factor Slug - also known as Snai2 - recruits epigenetic modifiers and regulates gene expression by an epigenetic mechanism; however, its epigenetic action has not been explored in leptin resistance. Here, we uncover a proobesity function of neuronal Slug. Hypothalamic Slug was upregulated in obese mice. LepRb+ cell-specific Slug-knockout (SlugΔLepRb) mice were resistant to diet-induced obesity, type 2 diabetes, and liver steatosis and experienced decreased food intake and increased fat thermogenesis. Leptin stimulated hypothalamic Stat3 phosphorylation and weight loss to a markedly higher level in SlugΔLepRb than in Slugfl/fl mice, even before their body weight divergence. Conversely, hypothalamic LepRb+ neuron-specific overexpression of Slug, mediated by AAV-hSyn-DIO-Slug transduction, induced leptin resistance, obesity, and metabolic disorders in mice on a chow diet. At the genomic level, Slug bound to and repressed the LepRb promoter, thereby inhibiting LepRb transcription. Consistently, Slug deficiency decreased methylation of LepRb promoter H3K27, a repressive epigenetic mark, and increased LepRb mRNA levels in the hypothalamus. Collectively, these results unravel what we believe to be a previously unrecognized hypothalamic neuronal Slug/epigenetic reprogramming/leptin resistance axis that promotes energy imbalance, obesity, and metabolic disease.

Anti-Oxidant and Anti-Inflammatory Effects of Astaxanthin on Gastrointestinal Diseases.

A moderate amount of reactive oxygen species (ROS) is produced under normal conditions, where they play an important role in cell signaling and are involved in many aspects of the immune response to pathogens. On the other hand, the excessive production of ROS destructs macromolecules, cell membranes, and DNA, and activates pro-inflammatory signaling pathways, which may lead to various pathologic conditions. Gastrointestinal (GI) mucosa is constantly exposed to ROS due to the presence of bacteria and other infectious pathogens in food, as well as alcohol consumption, smoking, and the use of non-steroidal anti-inflammatory drugs (NSAID). Prolonged excessive oxidative stress and inflammation are two major risk factors for GI disorders such as ulcers and cancers. Bioactive food compounds with potent anti-oxidant and anti-inflammatory activity have been tested in experimental GI disease models to evaluate their therapeutic potential. Astaxanthin (AST) is a fat-soluble xanthophyll carotenoid that is naturally present in algae, yeast, salmon, shrimp, and krill. It has been shown that AST exhibits protective effects against GI diseases via multiple mechanisms. Residing at the surface and inside of cell membranes, AST directly neutralizes ROS and lipid peroxyl radicals, enhances the activity of anti-oxidant enzymes, and suppresses pro-inflammatory transcription factors and cytokines. In addition, AST has been shown to inhibit cancer cell growth and metastasis via modulating cell proliferation-related pathways, apoptosis, and autophagy. Considering the potential benefits of AST in GI diseases, this review paper aims to summarize recent advances in AST research, focusing on its anti-oxidant and anti-inflammatory effects against gastric and intestinal ulcers and cancers.

Colorectal cancer mortality trends in the era of cancer survivorship in Korea: 2000-2020.

PURPOSE: Korea has implemented an early screening for colorectal cancer since 2004. However, it is not known whether this has translated into improved survival over the years. METHODS: We acquired colorectal cancer mortality data from the Cause of Death Statistics in Korea from 2000 to 2020. We characterized the data into year of death, cancer-specific loci, and age group. We analyzed age-standardized mortality rates (ASMR) according to year of death, age group, and primary location to find trends in colorectal cancer mortality over a 20-year period. RESULTS: The crude mortality rate of colorectal cancer increased from 8.78 per 100,000 in 2000 to 17.27 per 100,000 in 2020. The second decade was slower in increments compared to the first decade. ASMR showed a decrease over the second decade after an initial increase in the first decade. The decrease was primarily from the lowering of ASMR for rectosigmoid cancers. Age group analysis showed a lowering of ASMR mainly in the 45-59-year, 60-74-year, and ≥ 75-year age groups; however, 0-29-year and 30-44-year age groups showed generally unchanged ASMR over the total period. CONCLUSION: After a brief incline of age-specific mortality of colorectal cancers during the early 2000s, colorectal cancer mortality has gradually been decreasing in the past decade. This was mainly due to decreased mortalities in rectosigmoid colon cancers especially in the age groups that were the target of early screening.

Clinical outcomes of surgical management for recurrent rectal prolapse: a multicenter retrospective study.

Purpose: There are few reports on outcomes following surgical repair of recurrent rectal prolapse. The purpose of this study was to examine surgical outcomes for recurrent rectal prolapse. Methods: We conducted a multicenter retrospective study of patients who underwent surgery for recurrent rectal prolapse. This study used data collected by the Korean Anorectal Physiology and Pelvic Floor Disorder Study Group. Results: A total of 166 patients who underwent surgery for recurrent rectal prolapse were registered retrospectively between 2011 and 2016 in 8 referral hospitals. Among them, 153 patients were finally enrolled, excluding 13 patients who were not followed up postoperatively. Median follow-up duration was 40 months (range, 0.2-129.3 months). Methods of surgical repair for recurrent rectal prolapse included perineal approach (n = 96) and abdominal approach (n = 57). Postoperative complications occurred in 16 patients (10.5%). There was no significant difference in complication rate between perineal and abdominal approach groups. While patients who underwent the perineal approach were older and more fragile, patients who underwent the abdominal approach had longer operation time and admission days (P < 0.05). Overall, 29 patients (19.0%) showed re-recurrence after surgery. Among variables, none affected the re-recurrence. Conclusion: For the recurrent rectal prolapse, the perineal approach is used for the old and fragile patients. The postoperative complications and re-recurrence rate between perineal and abdominal approach were not different significantly. No factor including surgical method affected re-recurrence for recurrent rectal prolapse.

Oncologic safety of laparoscopic surgery after metallic stent insertion for obstructive left-sided colorectal cancer: a multicenter comparative study.

BACKGROUND: Self-expanding metallic stents (SEMSs) are used as a bridge to surgery in patients with obstructive colorectal cancer. However, the role of laparoscopic resection after successful stent deployment is not well established. We aimed to compare the oncologic outcomes of laparoscopic vs open surgery after successful colonic stent deployment in patients with obstructive left-sided colorectal cancer. METHODS: In this multicenter study, 179 (97 laparoscopy, 82 open surgery) patients with obstructive left-sided colorectal cancer who underwent radical resection with curative intent after successful stent deployment were retrospectively reviewed. To minimize bias, we used inverse probability treatment-weighted propensity score analysis. The short- and long-term outcomes between the groups were compared. RESULTS: Both groups had similar demographic and tumor characteristics. The operation time was longer, but the degree of blood loss was lower in the laparoscopy than in the open surgery group. There were nine (9.3%) open conversions. After adjustment, the groups showed similar patient and tumor characteristics. The 5-year disease-free survival (DFS) (laparoscopic vs open: 68.7% vs 48.5%, p = 0.230) and overall survival (OS) (laparoscopic vs open: 79.1% vs 69.0%, p = 0.200) estimates did not differ significantly across a median follow-up duration of 50.5 months. Advanced stage disease (DFS: hazard ratio [HR] 1.825, 95% confidence interval [CI]: 1.072-3.107; OS: HR 2.441, 95% CI 1.216-4.903) and post-operative chemotherapy omission (DFS: HR 2.529, 95% CI 1.481-4.319; OS: HR 2.666, 95% CI 1.370-5.191) were associated with relatively worse long-term outcomes. CONCLUSION: Stent insertion followed by laparoscopy with curative intent is safe and feasible; the addition of post-operative chemotherapy should be considered after successful treatment.

Objective recovery time with end-to-side versus side-to-side anastomosis after laparoscopic right hemicolectomy for colon cancer: a randomized controlled trial.

BACKGROUND: Despite reports of the short-term benefits of end-to-side versus side-to-side anastomosis, we are aware of no prospective studies in which these methods were compared. We hypothesized the superiority of end-to-side over side-to-side anastomosis in terms of recovery after laparoscopic right hemicolectomy for colon cancer under an enhanced recovery program. METHODS: From September 2016 to August 2019, 130 patients were randomly allocated to receive end-to-side or side-to-side anastomosis at a single tertiary hospital in Korea. The primary outcome was the cumulative recovery rate seven days after surgery, defined as the percentage of patients who met all four recovery criteria: diet tolerance, no analgesia, safe ambulation, and an afebrile status. Student's t test, the Mann-Whitney U test, the χ2 test, and Fisher's exact test were used to compare variables, as applicable. RESULTS: The cumulative recovery rate at seven days did not differ between patients receiving end-to-side (92.3%, 60/65) or side-to-side anastomosis (92.3%, 60/65; P ≥ 0.999). The end-to-side and side-to-side groups had similar cumulative recovery rates at postoperative days 4, 5, and 6 (end-to-side vs. side-to-side: 41.5% vs 35.4%, P = 0.589; 73.8% vs 63.1%, P = 0.257; and 86.2% vs 81.5%, P = 0.634, respectively). None of the secondary endpoints differed for end-to-side vs. side-to-side anastomosis: the median length of postoperative hospitalization (5 [IQR 5-7] vs. 6 [IQR 5-7] days, respectively, P = 0.376), the 30-day complication rate (16.9% vs. 12.3%, respectively, P = 0.620), the enhanced recovery protocol failure rate (10.8% vs. 7.7%, respectively, P = 0.763), and the 30-day readmission rate (4.6% vs. 3.1%, respectively, P ≥ 0.999). CONCLUSIONS: End-to-side anastomosis was not superior to side-to-side anastomosis in terms of recovery criteria after laparoscopic right hemicolectomy. These findings do not provide evidence for a functional advantage of end-to-side compared to side-to-side anastomosis.

Oncologic comparison between nonradical management and total mesorectal excision in good responders after chemoradiotherapy in patients with mid-to-low rectal cancer.

PURPOSE: This study was performed to compare the oncologic outcomes between nonradical management and total mesorectal excision in good responders after chemoradiotherapy. METHODS: We analyzed 75 patients, who underwent 14 watch-and-wait, 30 local excision, and 31 total mesorectal excision, in ycT0-1N0M0 based on magnetic resonance imaging after chemoradiotherapy for advanced mid-to-low rectal cancer in 3 referral hospitals. The nonradical management group underwent surveillance with additional sigmoidoscopy and rectal magnetic resonance imaging every 3-6 months within the first 2 years. RESULTS: Nonradical management group had more low-lying tumors (P < 0.001) and less lymph node metastasis based on magnetic resonance imaging (P = 0.004). However, cT stage, ycT, and ycN stage were not different between the 2 groups. With a median follow-up period of 64.7 months, the 5-year locoregional failure rate was higher in the nonradical management group than in the total mesorectal excision group (16.7% vs. 0%, P = 0.013). However, the 5-year overall survival and disease-free survival rates of the nonradical management and total mesorectal excision groups were not different (95.2% vs. 93.5%, P = 0.467; 76.4% vs. 83.6%, P = 0.665; respectively). CONCLUSION: This study shows that nonradical management for ycT0-1N0 mid-to-low rectal cancer may be an alternative treatment to total mesorectal excision under proper surveillance and management for oncologic events.

Comparison of oncologic outcomes between patients with Lynch syndrome and sporadic microsatellite instability-high colorectal cancer.

PURPOSE: Long-term oncologic differences in outcome between groups of patients with Lynch syndrome (LS) colorectal cancer (CRC) and sporadic CRC with microsatellite instability-high (MSI-H) are the focus of investigation in the current study. METHODS: Patients registered in the Korean Hereditary Tumor Registry and 2 tertiary referral hospitals treated for stage I-III CRC between 2005 and 2015 were retrospectively analyzed. Detection for both groups was performed using pedigree, microsatellite instability, and mismatch repair (MMR) gene testing. Multivariate analyses for overall survival (OS) and disease-free survival (DFS) were conducted. RESULTS: Cases of LS (n = 77) and sporadic CRC with MSI-H (n = 96) were identified. LS CRC patients were younger in age and displayed tumor sidedness, typically involving left-sided colon and rectum, compared to patients with sporadic CRC with MSI-H. OS and DFS were lower for LS CRC relative to CRC with MSI-H (OS, 72.7% vs. 93.8%, P = 0.001; DFS, 71.4% vs. 88.5%, P = 0.001). In multivariate analyses, tumor sidedness, stage, and chemotherapy were independent factors for OS and DFS. LS CRC was a prognostic factor for poorer OS (hazard ratio, 2.740; 95% confidence interval, 1.003-7.487; P = 0.049), but not DFS. CONCLUSION: Our findings indicate that LS CRC is associated with poorer outcomes compared to sporadic CRC with MSI-H, presenting distinct clinical features. In view of the current lack of knowledge on genetic and molecular mechanisms, appropriate management taking into consideration the difficulty of identification of CRC with hypermutable tumors harboring heterogeneity is essential.

Quality of life after sphincter preservation surgery or abdominoperineal resection for low rectal cancer (ASPIRE): A long-term prospective, multicentre, cohort study.

BACKGROUND: The long-term effects of radical resection on quality of life may influence the treatment selection. The objective of this study was to determine whether abdominoperineal resection has a better effect on the quality of life than sphincter preservation surgery at 3 years after surgery. METHODS: This prospective, cohort study included patients who underwent radical resection for low rectal cancer. The primary outcomes were European Organisation for Research and Treatment of Cancer QLQ-C30 and CR38 quality of life scores 3 years after surgery, which were compared with linear generalised estimating equations, after adjustment for baseline values, a time effect, and an interaction effect between time and treatment. The secondary outcomes included sexual-urinary functions and oncological outcomes. The study was registered with ClinicalTrials.gov (NCT01461525). FINDINGS: Between December 2011 and August 2016, 342 patients were enrolled: 268 (78•4%) underwent sphincter preservation surgery and 74 (21•6%) underwent abdominoperineal resection. The global quality of life scores did not differ between sphincter preservation surgery and abdominoperineal resection groups (adjusted mean difference, 4•2 points on a 100-point scale; 95% confidence interval  [CI], -1•3 to 9•7, p = 0•1316). Abdominoperineal resection was associated with a worse body image (9•8 points; 95% CI, 2•9 to 16•6, p = 0•0052), micturition symptoms (-8•0 points; 95% CI, -14•1 to -1•8, p = 0•0108), male sexual problems (-19•9 points; 95% CI, -33•1 to -6•7, p = 0•0032), less confidence in getting and maintaining an erection in males (0•5 points on a 5-point scale; 95% CI, 0•1 to 0•8, p = 0•0155), and worse urinary symptoms (-5•4 points on a 35-point scale; 95% CI, -8•0 to -2•7, p < 0•0001). The 5-year overall survival was worse with abdominoperineal resection in unadjusted (92•2% vs 80•9%; difference 11•3%, hazard ratio 2•38; 95% CI, 1•27 to 4•46, p = 0•0052), but did not differ after adjustment. INTERPRETATION: In this long-term prospective study, abdominoperineal resection failed to meet the superiority to sphincter preservation surgery in terms of quality of life. Although the global quality of life scores did not differ between groups, this study suggests that sphincter preservation surgery can be an acceptable alternative to abdominoperineal resection for low rectal cancer, offering a better quality of life and sexual-urinary functions, with no increased oncological risk even after 3 years. FUNDING: Seoul National University Bundang Hospital, Korea.

Role of Leptin in the Digestive System.

Leptin is a pluripotent peptide hormone produced mainly by adipocytes, as well as by other tissues such as the stomach. Leptin primarily acts on the central nervous system, particularly the hypothalamus, where this hormone regulates energy homeostasis and neuroendocrine function. Owing to this, disruption of leptin signaling has been linked with numerous pathological conditions. Recent studies have also highlighted the diverse roles of leptin in the digestive system including immune regulation, cell proliferation, tissue healing, and glucose metabolism. Of note, leptin acts differently under physiological and pathological conditions. Here, we review the current knowledge on the functions of leptin and its downstream signaling in the gastrointestinal tract and accessory digestive organs, with an emphasis on its physiological and pathological implications. We also discuss the current therapeutic uses of recombinant leptin, as well as its limitations.

Author Correction: Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Is elevated microsatellite alterations at selected tetranucleotide repeats (EMAST)-negative/MSI-high colorectal cancer a distinct subtype of the disease?

BACKGROUND AND OBJECTIVES: Microsatellite instability (MSI) plays a prognostic and predictive role in colorectal cancer (CRC). Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), a novel type of MSI, was recently identified. METHODS: A retrospective analysis of a prospective cohort database was performed. Patients who attempted curative surgery for MSI-high (MSI-H) CRC and had available testing results of EMAST were included for analysis. The difference in clinical characteristics, immunohistochemistry profile, and 3-year recurrence-free and overall survival between EMAST-negative and EMAST-positive tumors was measured. RESULTS: EMAST status was successfully evaluated in 86 cases among patients who received EMAST testing, and only 16.3% (14/86) of these patients were EMAST-negative/MSI-H. Patients with EMAST-negative tumors were younger; their tumors exhibited well differentiation, less venous invasion, and greater mutS homolog 3 expression. There was no distant metastasis or cancer-specific death among EMAST-negative patients. Yet no statistically significant difference was found between the two groups in 3-year overall or recurrence-free survival. CONCLUSIONS: Patients with EMAST-negative/MSI-H CRC seem to have different clinicopathological characteristics. Future large-scale studies could clarify the role of EMAST genotype as a sub-classifier of MSI-H CRC.

Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease.

Leptin stimulates the sympathetic nervous system (SNS), energy expenditure, and weight loss; however, the underlying molecular mechanism remains elusive. Here, we uncover Sh2b1 in leptin receptor (LepR) neurons as a critical component of a SNS/brown adipose tissue (BAT)/thermogenesis axis. LepR neuron-specific deletion of Sh2b1 abrogates leptin-stimulated sympathetic nerve activation and impairs BAT thermogenic programs, leading to reduced core body temperature and cold intolerance. The adipose SNS degenerates progressively in mutant mice after 8 weeks of age. Adult-onset ablation of Sh2b1 in the mediobasal hypothalamus also impairs the SNS/BAT/thermogenesis axis; conversely, hypothalamic overexpression of human SH2B1 has the opposite effects. Mice with either LepR neuron-specific or adult-onset, hypothalamus-specific ablation of Sh2b1 develop obesity, insulin resistance, and liver steatosis. In contrast, hypothalamic overexpression of SH2B1 protects against high fat diet-induced obesity and metabolic syndromes. Our results unravel an unrecognized LepR neuron Sh2b1/SNS/BAT/thermogenesis axis that combats obesity and metabolic disease.